19-nor-9beta, 10alpha-delta4-androstenes



United States Patent 4 rUrNQB'QfiA" -MiANDRQSIENES A b rt B9 e a Athe'ma Qalin, Pier e C abth Mexic titt and John E wards Los Alt 'assig'norsf0 Syntex (Importation, Panama, 'Papama, a corporation Qgi Papama Y NoDrawing. Filed- Mar.8, '1965, :Ser. No. 438,065 Glaims priority,application Mexico, Dec. .4, 1961,

65,269 10 Claims. (Cl. 260397.3)

In this formula R represents a hydroxyl group or an acylqxy group, Rrepresents hydrogen or a lower alkyl, lower alkenyl or lower alkynylgroup containing up to 8 carbon atoms, inclusive, such as methyl, ethyl,propyl, vinyl, ethy-nyl, propynyl, butynyl, hexynyl, and the like, R andR taken' together represent a keto group, X represents hydrogen ormethyl, and Y represents hydrogen, fl-hydroxyl or a keto group, with Rbeing an acyloxy group when Y is a keto group.

The acyloxy and acyl groups referred to herein are preferably derivedfrom hydrocarbon carboxylic acids containing less than 12 carbon atoms.These acids can be saturated or unsaturated (including aromatic), andcan have straight or branched aliphatic, cycloaliphatic,cycloaliphatic-substituted aliphatic and aromatic-substituted aliphaticchains. In addition, they can be unsubstituted or substituted with oneor more functional groups, such as hydroxyl, ,alkoxy or amino groups,halogen atoms, and the like. Included among such ester groups areacetate, trimethylacetate, t-butylacetate, phenozryaeetate,aminoacetate, propionate, cyclopentylpropionate, pechloropropionate,valera te, enanthate, undecenoate and ben zgate ps-t I The novel11-desoxy-19-nor-913,loot-androstane derivatives of the presentinvention can be prepared by a process which can be illustratedschematically as follows:

In these formulas X has the same meaning as set forth hereinabove forEormula I, 132 represents a benzoyl group,

R represents a lower alkyl group, R represents hydrogen 91 an aeylgroup, and R represents a lower alkyl, lower alkenyl or lower ,al-kynylgroup containing up to 8 carbon atoms, inclusivel In practicing theabove-illustrated process, the 17-ben- 7 zoate of a 3.-lowerhydroc-arbonoXy-9-dehydroestradiol,

,benzoate (1; k methyl, X=hydrogen), is treated with a stream ofdiborane in solution in an inert organic solvent, e.g., an ether such asdioxane, tetrahydrofuran or the like, for a period of time in the orderof 1 to 3 hours, and the resulting organoboron compound is then treatedwith alkaline hydrogen peroxide, in the same solvent, to give thecorresponding lla-hydroxy steroid 2, e.g., B-methoxy- A estratriene1la,175-diol 17 benzoate (2; R =methyl, X=hydrogen). t

Oxidation of the thus-obtained lloc-hydroxy steroid with 8 N chromicacid in acetone solution gives the corresponding ll-keto steroid 3,e.g., 3-methoxy-A estratrien-17B-ol-l1-0ne 17-benzoate (3; R =methyl, X=hydrogen).

Upon treatment of this ll-one with a dilute solution of a strong base ina lower aliphatic alcohol, preferably 15% methanolic sodium or potassiumhydroxide, at reflux temperature for from about 5-24 hours, under aninert nitrogen atmosphere, the steric configuration at -9 is inverted,thus producing the corresponding QB-steroid 4, e.g., 3 methoxy-9B-A-estratrien-1713-01-1l-one 17-benzoate (4; R rnethyl, X=hydrogen).

The ll-keto function in this 9,8-steroid is then elimi nated by firstforming the corresponding l1-ethylenedi-,

thioketal 5, e.g., 3-methoxy-11-cycloethylenedithio-9B- A-estratrien-lZB-ol -l 7-benzoate (5; R =methyl, X=hydrogen t Thisll-ethylenedithioketal is then refluxed with Raney nickel in ethanol fora period of time in the order of 6 hours, thus giving the correspondingll-desoxy steroid 6, e.g., 3-methoxy-9B-A -estratrien-175-01 17-benzoate(6; R =methyl, X=hydrogen).

Reduction of the resulting 11-desoxy steroid under Birch conditions,using lithium in liquid ammonia, gives the A -dien-flfl-ol 7, e.g.,3-methoxy-9,8-A -estradien-17B-ol (7; R =methyl, X=hydrogen).

Acid hydrolysis of the thus-obtained A -dien-17,8 01 gives the19-nor-9/3,lQa-A androsten-17,8-01-3 one 8, e.g., 19-nor-9B,lOa-A-andrQsten-l7 3-ol-3-one itself (19- nor-9fl,lOu-testoster-on, R andX=hydrogen).

Oxidation of the l7fi-hydroxy group in this 9fi,10oc-Steroid, usingchromium trioxide in pyridine at room temperature, gives thecorresponding 3,17-dione 9, e.g., 19- 110F913,1Goc-A'andr0Sten6-3,l7-di0ne (9; X=hydrogen) Where the l7a-lower alkyl, loweralkenyl or lower alkynyl-17fl-hydroxy compounds of the present inventionare desired, the keto group at C-3 in thel7a-unsubstituted-17fl-ol-3-0ne 8 is protected by formation of an enolether 10, e.g., 3-ethoxy-19-nor-95,l0ot-A androstadien- 176-01 (10; R=ethyl, X=hydrogen), and the free 17 8- hydroxy group in this 3-enolether-17B-ol is then oxidized, using chromium trioxide in pyridine, togive the corresponding 3-enol ether-l7-one 11, e.g.,3-ethoxy-l9-nor-9l8,

10ot-A -androstadien-l7-one (l1; R =ethy1, X=hydro-,

gen). Next, this 3-enol ether-Tone is reacted with a hydrocarbonmagnesium halide, following which the 3-enol ether group is hydrolyzed,thus giving the 17a-lower alkyl, lower alkenyl or lower alkynyl-l7B-ol12, e.g., 170amethyl-19-nor-9fi,IOa-M-androsteu-17,8-ol-3-one (12; R andX=hydro'gen, R =methyl).

Alternatively, the 3-enol ether-17-one 11 can be formed from the3,17-dione 9.

Esterification of the 17a-unsubstituted-17B-ols 8 with acid anhydridesor chlorides, preferably those containing less than 12 carbon atoms, inpyridine solution, gives the corresponding 17-acylates. Thus, forexample, esterifica- 'tion of 19-n0r-9;i,IDOL-testosterone with aceticanhyd ride .in pyridine gives the corresponding 17-acetate (8;1R

acetyl, X=hydrogen). Esterification of'the 17OL-1OWC1' alkyl, loweralkenyl 0 ---lower alkynyl-l7fi-ols 12 is efiected with acid anhydridesin benzene solution in the presence of p-toluenesulfonic acid, followedby acid treatment of the acylation reaction tmixture, e.g., using a 15%methanolic solution of con-1 centrated hydrochloric acid and boiling forfromabout 1 hour to about} hours, .to hydrolyze the 3-enol acylategrouping formed during the reaction and regenerate the A -3-ketostructure. Thus, for example, by esteritying17a-ethynyl-l9-nor-9fl,mot-testosterone with acetic anhydride in benzenesolution in the presence of p-toluenesulfonic acid, and then adding a 2%methanolic solution of concentrated hydrochloric acid to the acetylationreaction mixture and boiling for 2 hours, the corresponding 17- acetate(12; R =acetyl, R =ethynyl, X=hydrogen) is formed.

The novel 1loxygenated-19-nor-9B,10a-androstane derivatives of thepresent invention can be prepared by processes which can be illustratedschematically as follows:

In these formulas X, R R and Bz have the same meanings as set forthhereinabove for Formulas I, 1 and X11- and R represents an acyl group.

In, practicing the above-illustrated process, the starting 15 6 material1 2v A -estr tetraenrol-I-Z-Qne (1 3s; X=hydrogen), is converted to.-the corresponding 17- ketal 1,4, e.g., 17-cycloethylenedioxy-A-estratetraen-3sol (14; X=hydrogen),, by treatment with ethylene glycolin benzene. sol tion; in the. pres nce f. p-toluenesulfonie. acid.v I tThe thus-obtained: 17-ketal is treated with diboranein tetrahydrofuranor dioxane solution, and then with alkaline hydrogen peroxide, in themanner described hereinabove, to produce the corresponding 3,11a-di011,5, e.g-,, 17-cycloethylenedioxy-Al -estratriene-S,lzlet-diol (l5,X=hydrogen) By subjecting this 3,1101-(1101 to the Schotten-Baumannreaction, i.e., using benzoyl chloride and aqueous sodium hydroxide at.room temperature, the corresponding 3.-benzoate 16, e.g.,17-cycloethylenedioxy-Am -estratrienlilac-dbl 3-benzoate 1,6;,X=hydrogen), is obtained,

Oxidation of the lla-hydroxyl group in the thus-ob;- tained 3-benzoateis then accomplished by using chromium trioxide in pyridine at roomtemperature, thus giving the correspondingll-keto steroidv 17, e.g.,17-cycloethylenedioxy-A -estratrien-3,-ol-ll-one 3-benzoate (17; X:hydrogen).

Upon treatment of this l1-onewith a dilute solution of .a strong base ina: lorweraliphaticalcohol, preferably 5% .methanolic sodium or potassiumhydroxide, at reflux temperature, under an inert nitrogen atmosphere,for from about 5-24 hours, the steric configuration at C-9 is invertedand the benzoyloxy group at C-3 is hydrolyzed, thus producing the3-hydroxy-9 3-steroid 18, e.g;, 17-cycloethylenedioxy-9fi-A i-estratrien 3. 01,-11- one (18,; X=hydrogen).

Treatment of t-ln's. 3-hydroxy 9fi-steroid. with dimethyl sulfate inacetone solution in the presence of potassium carbonate gives the;corresponding S-methyl ether 19,

e.g., 3-methoxy-17-cycloethylenedioxy-9B-A -estratrien-l l-one (19; X=hydrogen).

The ll-keto group in the thus-produced 3-methyl ether is reduced bydissolving the steroid in an inert organic solvent, e.g., an ether suchas dioxane or tetrahydrofuran, and the like, and reacting under neutralconditions with a metal hydride, e.g., lithium aluminum hydride, lithiumtri(t-butoxy)aluminum hydride, and the like, thus giving a mixture of1111- and llB-alcohols 20, e.g., 3-methoxy-l7- .cycloethylenedioXy-9 3-A-estratrien-1lot-o1 and 3- methoXy 17 cycloethylenedioXy-9 S-A-estratrien- 11 3-01 (20; X=hydrogen), which can either be separatedchromatographically or by fractional crystallization (as is the casewith any of the subsequently obtained mixtures of llccand 11 3-ols) atthis point, or used as such in the remaining steps.

Acid hydrolysis of the thus-obtained S-methoxy-llt and/or B)-ol--17-ketal, using 1-5-% hydrochloric acid in methanol or aqueousacetone, gives the corresponding 17- When 17u-unsubstituted-17,8-ols aredesired, the resulting 17-keto steroid can be reduced withlithium,aluminum hydride or sodium borohydride under neutral conditions in aninert organic solvent, -e.g., an ether such as dioxane, tetrahydrofuran,and the like, thus givingthe corresponding 175-01 '22, e.g.,3-methoXy-9p-A -estratriene- 11,3,17fl-diol (22; R and X=hydrogen),.

When the Hot-lower alkyl, alkenyl or alkynyl-fle-ols are desired, thel'l-keto steroid 21 is reacted with the appropriate hydrocarbonmagnesium halide in the manner described hereina-bove, thus giving thecorresponding 17mlower alkyl, alkenyl oralkynyl-l'lfl-ol 22, e.g.,3-methoxy- 17a-methyl-9fiFA -estratriene-l15,17,3-diol (22; R. methyl,X=hydrogen).

Reduction of the l7fi-hydroxy steroid 22' under Birch conditions, usinglithium in liquid ammonia, gives the A -dien-flfi-ol 23, e.g.,3-methoxy-9 8-A -estradiene 1l; 8,17,6-d:io1 (23'; R and X=hydrogen).

Acid hydrolysis of the thus-obtained, A -diene-l 1,

17,8-diol gives the corresponding 19-nor-9fl,1 'wA-androstene-11fl,17,3-diol-3-one (24; R and X hydrogen).

Where there is no 17m-substituent, the thus-obtained 11,

'17B-diol can be oxidized, using chromium trioxide in gen).

The 11 fl-hydroxyl group in this 17-monoacetate can be oxidized, usingchromium trioxide in pyridine at room temperature, thus giving thecorresponding ll-keto steroid 27, e.g., 19-nor-9fl,1Oa-A-androsten-17B-ol-3,1l-dione l7- acetate (27; R =acetyl, X=hydrogen).

Where the 115,17B-diol 24 has a l7a-substituent, it can be converted tothe corresponding 17-monoester by first reacting with an acid anhydridein benzene solution in the presence of p-toluenesulfonic acid to givethe corresponding 3-enol acylate-A -11,17-diacylate 28. Thus, forexample, the reaction of 17a-methyl-19-nor-9fl,10a-A-androstene-l1fi,17fi-diol-3-one with acetic anhydride in benzenesolution in the presence of p-toluenesulfonic acid gives17a-methyl-19-nor-9fi,10a-A -androstadiene-3J 1 5,

17fi-triol 3,11,17-triacetate (28; R ==methyl, R =acetyl,

X= hydrogen).

- This 3-enol acylate is then converted to the corresponding A -3-keto 11,17-diester 29, e.g., l7a-methyl-19-nor- 9fl,10a A-androstene-11,8,175-diol-3-one 11,17-diacetate (29; R =methyl, R=acetyl, X=hydrogen), by hydro1ysis with an aqueous methanolic 5%hydrochloric acid solu- 'tion.

By hydrolyzing the thus-obtained 11,17-diester with a 1-5% solution ofsodium or potassium bicarbonate in aqueous methanol at 0-20 C. for 1-18hours, the corresponding 17-monoester 30, e.g. 17a-rnethyl-19-nor-9B,10oz n -androstene 116,17/8-diol-3-one 17-acetate (30;

R methyl, R =acetyl, X=hydrogen), is obtained.

Oxidation of this l7-monoester with chromium trio-xide "in pyridine atroom temperature gives the corresponding 'll -keto steroid 31, e.g.,17a-methyl-19-nor-9p,10a-A -an 'drostene-17B-ol-3,1l-dione l7-acetate(31; R =acetyl,

R =methyl, X=hydrogen) By reducing the3-methoxy-17-cycloethylenedioxy-9fi- A -estratrien-1l-ol 20 under Birchconditions, using lithium in liquid ammonia, the corresponding 2,5 (10)-diene 32, e.g., 3 methoxy 17 cycloethylenedioxy-9B- A F-estradien-1113-01 (32; X=hydrogen), is obtained.

Acid hydrolysis of this A -diene in the manner de- "scribed hereinaboveremoves the productive groupings at C-3 and C-17, thus giving thecorresponding 3,17-

dione (33; X=hydrogen).

The novel Hot-unsubstituted and 17a-lower alkyl steroids represented byFormula I hereinabove are anabolic-androgenic agents having a favorableanabolic/androgenic ratio. In addition, they have anti-estrogenicactivity,

suppress the output gonadotr'ophin by the pituitary gland, and lowerblood chloesterol levels.

The novel l7a-lower alkenyl and 17a-lower alkynyl 'steroids representedby Formula I hereinabove are progestational agents which also haveestro'geuic activi y, and 'thus are useful in fertility control inhumans and animals. "They also suppress the output of gonadotrophin bythe pituitary gland .and lower blood cholesterol levels.

In order that those skilled in the art can'more fully understand thepresent invention, the following examples are set forth. These examplesare given solely for the purpose of illustrating the invention, andshould not be considered as expressing limitations unless so set forthin the appended claims. I

8 Example I A stream of diborane was passed through a solution of 15grams of 3-methoxy-A -estratetraen-17/3-01 17-benzoate in 375 cc, ofanhydrous tetrahydrofuran for 3 hours, following which the reactionmixture was allowed to stand at room temperature overnight underanhydrous conditions. Following this reaction period excess diborane wasdestroyed by the addition of water, and the resulting solution was thencooled to -5 C. and treated dropwise with 750 mg. of sodium hydroxide in6 cc. of water and cc. of 35% hydrogen peroxide. The resulting reactionmixture was stirred for 1 hour, then neutralized with acetic acid andextracted with methylene dichloride. The thus-obtained extract waswashed with water, dried over anhydrous sodium sulfate and evaporated todryness. Chromatography of the resulting residue on 750 grams of washedalumina, followed by crystallization of the solid fractions fromacetone/hexane, gave 3-methoxy-A estratriene- 11a,17B-diol 17-benz0ate.

By repeating this procedure using 1-methyl-3-methoxy- A estratetraen 178 ol 17-benzoate as the steroid starting material, 1-methyl-3-methoxy-Aestratriene-11a,17l3-diol 17-benzoate was obtained.

Example 11 A solution of 10 grams of 3-methoxy-A-estratriene-1la,175-diol 17-benzoate in 200 cc. of acetone, containedunder an inert nitrogen atmosphere, was cooled to 0 C. and treated, withstirring, with an 8 N solution of chromic acid (prepared by admixing 26grams of chromium trioxide with 23 cc. of concentrated sulfuric acid andthen diluting with water to cc.) until the color of the reagentpersisted in the reaction mixture. At this point, the reaction mixturewas stirred for an additional 5 minutes at 0-5 C., then diluted withwater. The resulting precipitate was collected by filtration, washedwith water and dried under vacuum, thus affording a crude product which,upon recrystallization from acetone/hexane, gave 3-meth0xy-A-estratrien-17,9- ol-ll-one 17-benz0ate.

By repeating this procedure using l-methyl-3-rnethoxy- A estratricne1la,17,8 diol 17-benzoate as the steroid starting material,1-methyl-3-methoxy-A estratrien-17B-ol-11-one 17-benzoate was obtained.

Example III Example -IV A solution of 5 grams of 3-rnethoxy-95-A-estratrien-l7,8-ol-11-one 17-benzoate in 100 cc. of glacial acetic acidcontaining 5 cc. of ethanedithiol was admixed with 4 cc. of a saturatedsolution of hydrochloric acid in acetic acid, and the resulting reactionmixture was allowed to stand at room temperature for 4 hours. Followingthis reaction period the reaction mixture was diluted with water andextracted with ethyl acetate. The thus-obtained 1 extract was washedwith an aqueous 5% sodium bicarbonate solution and then with water untilneutral, then dried over anhydrous sodium sulfate and evaporated todrynessunder vacuum. Recrystallization of the resulting to the filtrate.The filtrate and washings were then evaporated, to dryness and theresulting residue was dissolved in chloroform and washed with dilutehydrochloric acid, then with an aqueous sodium carbonate solution andfinally with water until neutral. The neutral solution was then driedover anhydrous sodium sulfate and evaporated to dryness.Recrystallization from acetone/hexane gave 3-methoxy-9fl-A-estratrien-1713-01 l7-benzoate.

By repeating this entire procedure using 1-methyl-3- vme thoxgy-9 3-A-estratrien-17B-ol-1'1-one 17-benzoate as the steroid starting material,1-methyl-3-methoxy-1lcycloethylenedithio-9fi-A -estratrien-17fl-ol 17benzoate and then 1-methyl-3-meth0xy-9B-A -estratrien- 175-01l7-benzoate, respectively, were obtained.

Example V A cold solution of 2 grams of 3-methoxy-9 8-Aestratrien-17fl-ol l7-benzoate in 250 cc. of anhydrous diethyl ether wasslowly added, with stirring, to a solution of 2.6 grams of lithium metalin 300 cc. of liquid ammonia, and the resulting reaction mixture wasstirred, following this addition, for 30 minutes. At this point 60 cc.of absolute ethanol were cautiously added (until decolorizationoccurred), and then the ammonia and diethyl ether were removed byevaporation. Water was then added and the resulting solid was collectedby filtration, washed with water and dried, thus giving 3-methoxy-9fl-AV estradien-l7B-ol.

By repeating this procedure using 1-methyl-3-methoxy- 9fi-A-estratrien-17fi-ol 17-benzoate as the steroid starting material,l-methyl-3-methoxy-9p Alum) estradien-l7;8-ol was obtained.

Example VI The 3-methoxy-9fi-A -estradien17fl-ol-obtained as describedin Example V hereinabove was dissolved in 75 cc. of methanol and admixedwith 40 cc. of 3 N hydrochloric acid, and the resulting reaction mixturewas refluxed for 20 minutes. Following this reaction period the reactionmixture was cooled to room temperature and poured into ice water. Thethus-formed precipitate was collected by filtration, washed with waterand dried. Chromatography of the thus-obtained crude product on 50 timesits weight of washed alumina gave 19-nor- 9B,1Oa-A-androsten-l7fl-ol-3-one (l9-nor-9B,10ot testosterone) By repeating thisprocedure using l-methyl-3-methoxy- 9 8-A -estradien-17 8-01 as thesteroid starting material, let-methyl-l9-nor-9fi,10tx-Aandrosten-17/3ol-3-one (let-methyl-l9-nor-913,wot-testosterone) wasobtained.

Example VII A solution of 1 gram of19-nor-9fi,lOu-M-androstenl7fl-ol3-one in 20 cc. of pyridine was admixedwith 1 gram of chromium trioxide in 20 cc. of pyridine, and theresulting reaction mixture was allowed to stand at room temperatureovernight. Following this reaction period the reaction mixture wasdiluted with ethyl acetate and filtered through Celite. The filtrate wasthen washed with water, dried over anhydrous sodium sulfate andevaporated to .dryness. Crystallization from acetone/hexane gave 19-nor-9,8,l0a-A -androstene-3,l7-dione.

By repeating this procedure using 1a-methyl-19-nor-9B,lOwM-androsten-l7/3-ol-3-one as the steroid starting material,1a-methyl-19-nor-9p,wot-A androstene 3,17- dione was obtained.

Example VIII A solution of 5 grams of 19-nor-9B,IOa-M-androsten-17;,B-ol-3-one in 200 cc. of anhydrous, peroxide-free dioxane wasadmixed with 6 cc. of freshly distilled ethyl orthoformate and 4 gramsof p-toluenesulfonic acid, and the resulting reaction mixture wasstirred at room tem- Perature for 15 minutes and then allowed to standat room temperature for an additional 30 minutes. At this point, 4 cc.of pyridine were added and the solution was then diluted with water. Theresulting precipitate was collected by filtration, washed with water andair-dried. Recrystallization from acetone/hexane gave 3 -ethoxy-1-.9-nor- .9 8,lDwA -androstadien-1773-01.

By repeating this procedure using 1amethyl-19-nor-95,10a-M-androsten-17;3-ol-3-one as the steroid starting material,1a-methyl-3-ethoxy-19-nor-9B,l0a-A -androstadien-17;8-ol was obtained.

Example IX The 3-enol ethers prepared as described in Example VIIIhereinabove were oxidized, using chromium trioxide in pyridine in themanner described in Example VII hereinabove, thus giving3-ethoxy-l9-nor-9 3,l0a-A -androstadien-l7-one and1a-methyl-3-ethoxy-l9-nor-9,B,mot-A an-drostadien-l7-one, respectively.

Example X A solution of 1 gram of 3-ethox-y-l'8-nor-9fi,mot-Aandrostadien-17-one in 250 cc. of thiophene-free benzene was admixedwith 27.5 cc. of a 4 N solution of methylmagnesium bromide in diethylether, and the resulting reaction mixture was refluxed, excludingmoisture, for 3 hours. Following this reaction period the reactionmixture was cooled to room temperature, cautiously poured into a dilutehydrochloric acid solution, and then extracted with ethyl acetate. Thethus-obtained extract was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure, thus giving anoily residue which was then dissolved in 20 cc. of

.A -androsten-17,8-01-3-one was obtained.

Similarly, by repeating this entire procedure using the .two. steroidstarting materials just mentioned and replacing methylmagnesium bromidewith equivalent amounts of ethylmagnesium bromide, vinylmagnesiumbromide, ethynylmagnesium bromide and propargylmagnesium bromide, thecorresponding Not-substituted steroids, namely,

respectively, were obtained.

"1 1 Example XI A mixture of 1 gram of 19-nor-9fi,lflu-A androsten-17fl-ol-3-one, 4 cc. of pyridine and 2 cc. of acetic anhydride wasallowed to stand at room temperature overnight. Following this reactionperiod the reaction mixture was poured into ice water and the resultingprecipitate was collected by filtration, washed with water and dried.Crystallization from acetone/hexane gave 19-nor- 9p,10rx-A-androsten-175-ol-3-one 17-acetate.

By repeating this procedure using la-methyl-19-nor- 9/3,l0a-A-androsten-l7fl-ol-3-one as the steroid starting material, thecorresponding 17-acetate was obtained.

Similarly, by repeating this procedure using each of the steroidstarting materials just mentioned and replacing acetic anhydride withpropionic, cyclopentylpropionic and caproic anhydride, respectively, thecorresponding 17-propionates, -cyclopentylpropionates and -caproateswere obtained.

Example XII To a solution of 2 grams of 17a-methyl-l9-nor-9B,101x- A-androsten-l7fi-ol-3-one in 40 cc. of anhydrous benzene there were added400 mg. of ptoluenesulr"onic acid vand 4 cc. of acetic anhydride, andthe resulting reaction mixture was allowed to stand at room temperaturefor 24 hours. Following this reaction period the reaction mixture waspoured into ice water and stirred to efiect hydrolysis of excess aceticanhydride. Next, the benzene layer was separated, washed with an aqueous10% sodium carbonate solution and then with water, then dried tratedhydrochloric acid, and the resulting reaction mixture was then refluxedfor 2 hours. Following this reaction period the reaction mixture wascooled, neutralized with aqueous sodium bicarbonate solution and dilutedwith water. The resulting precipitate was collected by filtration,washed with water and dried. Chromatography on alumina followed byrecrystallization from diethyl ether/hexane gavel7a-methyl-19-nor-9fi,l0a-A -androsten-17fi-ol-3-one 17-acetate.

By repeating this entire procedure using the remaining Not-substitutedsteroids prepared as described in Example X hereinabove, thecorresponding 17-acetates were obtained.

nates and -,caproates were obtained.

Example XIII A mixture of 1 gram of A -estratetraen-3- ol-17-0ne, 25 cc.of dry benzene, cc. of ethylene glycol and 50 mg. of p-toluenesulfonicacid monohydrate was refluxed for 16 hours, using a water separator toremove the water formed during the reaction. Folowing this'reactionperiod the reaction mixture was washed with an aqueous sodiumbicarbonate solution and then with water, then dried over anhydroussodium sulfate and evaporated to dryness. Recrystallization fromacetone/ hexane gave 17-cycloethylenedioxy A -estratetraen-3-ol.

By repeating this procedure using l-methyl-A m--estratetraen-3-ol-17-one as the steroid starting material,l-methyl-l7-cycloethylenedioxy A -estratetraen-3-ol was obtained.

' Example XIV The 17-ketals prepared as described in Example XIIIhereinabove were treated with diborane in tetrahydrofuran solution andthen with alkaline hydrogen peroxide in the manner described in ExampleI hereinabove, thus giving 17-cycloethylenedioxy-A estratriene-3,11adioland 1-methyl-l7-cycloethylenedioxy A -estratriene-3,11a-diol.

Example XV On gram of 17-cycloethylenedioxy-A -estratriene- 3,1loc-di0lin ml. of an aqueous 10% solution of sodium hydroxide was admixed atroom temperature, with stirring, with 20 molar equivalents of benzoylchloride. The resulting precipitate was collected by filtration, washedwith water until neutral and recrystallized from acetone/hexane, thusgiving 17 cycloethylenedioxy- A -estratriene-3,1la-diol 3-benzoate.

By repeating this procedure using 1-methyl-17-cycloethylenedioxy-A-estratriene-3,1lot-diol as the steroid starting material, thecorresponding 3-benzoate was obtained.

Example XVI 17-cycloethylenedioxy A -estratriene-3,1lot-diol andcorresponding l-methyl steroid were oxidized, using chromium trioxide inpyridine in the manner described in Example VII hereinabove, thus giving17-cycloethylenedioxy-A -estratrien 3-ol-11-one 3-benzoate andl-methyl-l7-cycloethylenedioxy A -estratrien-B-olll-one 3-benzoate.

Example XVII The ll-keto steroids prepared as described in Example XVIhereinabove were treated with a 1% methanolic r potassium hydroxidesolution in the manner described in Example III hereinabove, thus giving17-cycloethylenedioXy-9B-A -estratrien-3-ol-1l-one and l-methyl-17-cycloethylenedioxy-9fi A estratrien-3-ol-11- one, respectively.

Example XVIII A mixture of 5 grams of 17-cyc1oethylenedioXy-9fi- A-estratrien-3-ol-ll-one, 25 cc. of acetone, 70 grams of potassiumhydroxide and 37.5 cc. of water was treated dropwise, With stirring,with 10 cc. of dimethyl sulfate, and the resulting reaction mixture wasstirred, following this addition, for 45 minutes at room temperature.Following this reaction period the reaction mixture was poured into adilute hydrochloric acid solution and the resulting precipitate wascollected by filtration, washed with water until neutral and dried.Recrystallization from chloroform/methanol gave3-methoxy-l7-cycloethylenedioxy-9,8-A -estratrien-1l-one.

By repeating this procedure using l-rnethyl-17-cycloethylenedioxy-9B-A-estratrien-3-cl-ll-one as the steroid starting material, thecorresponding 3-1nethyl ether was obtained.

Example XIX A solution of 1 gram of3-methoxy-17-cycloethylenedioxy-9,3-A -estratrien-1l-one in 30 cc. ofanhydrous tetrahydrofuran Was slowly added, with stirring, to asuspension of 1 gram of lithium aluminum hydride in 50 cc. of anhydroustetrahydrofuran, and the resulting reaction mixture was refluxed for 2hours. Following this reaction period the reaction mixture was cooledand excess lithium aluminumhydride was destroyed by the addition of 5cc. of ethyl acetate and 2 cc. of water. Next, a saturated solution ofsodium sulfate and solid sodium sulfate were added, the inorganicmaterial was filtered off and washed with hot ethyl acetate, and thesewashings Were added to the filtrate' The filtrate was then evaporated todryness and the resulting residue was crystallized fromcycloethylenedioxy-9fifi -estratrien-11 x-ol and 3- methoxy-17cycloethyleuedioxy 93- A -3estratrierr- 1113-01.

Similarly, by repeating this procedure using l-methyl-3-methoxy-17-cycloethylenedioxy 9/3-A -estratrienll-one as the steroidstarting material, a. mixture of the corresponding 110:.- and llfi-olswas obtained.

The thus-obtained mixtures of llocand llfi-ols were then separated intothe individual isomers by chromatography on alumina.

. Example XX A solution of 1 gram of3-rnethoxy-17-cycloethylenedioxy-918-Al- -estratrien-1Ifi-ol in 50 cc.of acetone was admixed with 0.2 cc. of concentrated hydrochloric acid,and. the resulting reaction mixture was allowed to stand at roomvtemperature overnight. Following this reaction period the reactionmixture was poured into water and extracted with methylene dichloride.The thus-obtained extract was washed Withwater until neutral, then driedover anhydrous sodium sulfate and evaporated to dryness. Crystallizationfrom acetone/hexane gave 3- methoxy-9fl-A -estratrien-1 1 B-ol-l'l-one.

B'y repeating this procedure using 1-methyl-3-methoxy-17-cycloethylenedioxy 9fi-A -estratrien-1lfi-ol as the steroid startingmaterial, 1-methyl-3-methoxy-9B-A estratrien-11fl-o1-17-one wasobtained.

Example XXI The 17-ones prepared as described in Example XX hereinabovewere reduced, using lithium aluminum hydride in tetrahydrofuran solutionin the manner described in Example XIX hereinabove, thus giving3-methoxy-9f3- A -estratriene-1113,17fl-diol and 1-rnethyl-3-meth0xy-9B-A -estratriene-1lfl,l7[3-diol.

Example XXII The 17-ones prepared as described in Example XX hereinabovewere reacted with 'methylmagnesiurn bromide, ethylmagnesium bromide,vinylmagnesium bromide, ethynylmagnesiurn bromide andpropargylmagnesiurn bromide in dethyl ether in the manner described inExample X hereinabove, thus giving the corresponding 17OL-Sl1bStltUtedsteroids, namely,

3-methoxy-17a-methyl-9fl-A -estratriene-1 15,1713- diol,3-methoxy-17u-ethyl-9B-A -estratriene-1113,17fi-diol,3-methoxy-17a-vinyl-9fl-A -estratriene-1 15,17/3-diol, 3-methoxy-17a-ethynyl-9p3-A -estratriene1 13,175

diol, 3-methoxy-17a-propargyl-9B-A 1 -estratriene-l 113, 17,8-

diol, 3-methoxy-1,17a-dimethyl 9fl-h m -estratriene- 115,17fl-diol, Y pI 1-methyl-3-methoxy-17a-ethyl-9fl-A =estratriene- 115,17B-diol, j

1-methyl-3-methoxy-17a-Vinyl QB- A -estratrieneene-11p,17fi-diol,respectively.

Example XXIII The 175-hydroxy steroids prepared as described in ExamplesXXI and XXII hereinabove were reduced, using lithium in liquid ammoniain the manner described in Example V hereinabove, thus giving thecorresponding 7 A -dienes, namely,

3-methoxy-9fl-A -estradiene-l 1,8,l7B-diol, 1-methyl-3-methoxy-9;8-A-estradiene-115,17,8-diol, 3-rnethoxy-17a-methyl-9 8-A -estradiene-11,8,17,8-dio1, 3-methoxy-17a-ethyl-9fl-A -estradiene-1 1,3,175-diol,B-methoxy-17a-vinyl-9B-A -estradiene-1 1fl,17;3-diol,

3 -methoxy-17a-ethynyl-9 3-A -estradiene-1 15,17,3-dio1,

i-methoxy-17u-propargyl-9/3-A -estradiene-1 1B,17 8- diol,

3-methoxy-1'fa-dirnethylp-A -estradiene-l 15,17,9-

diol,

1-rnethyl-3-methoxy-17a-ethy1-9fi A -estradiene- 11B,17;3-dio1,

1-methyl-3 -methoxy1,7a-ethynyl-9B-A -estradiene- 11,8,17B-diol, and

1-methy1-3 -methoxy-17'or-propargyl-9, fl-A -estradiene- 1 1p,17fl-diol,respectively.

Example XXIV The A -dienes prepared as described in Example XXIIIhereinabove were hydrolyzed in the manner described in Example VIhereinabove, thus giving Example XXV 19-nor-9p,10u-A -androstene11,6,1715' diol-3-one and the corresponding lot-methyl compound wereoxidized, using chromium trioxide in pyridine in the manner described inExample VII hereinabove, thus giving 19-nor- 9B,10u-A-androstene-3,11,17-trione and 1a-methyl-19- nor-9f ,10ot-A-androstene-3,1l,17-trione.

Example XXVI 19-nor-9/3,10a-A -androstene-1 13,17/i-diol-3-one and thecorresponding lot-methyl compound were esterified, using 1.1 mols ofacetic anhydride in pyridine, in the manner described in Example XIhereinabove, thus giving 1-9-nor- 9,8,10a-M-androstene-11/8,17Bdiol-3-one 17 acetate and 1u-methyl-19-nor-9,8,IOa-M-andmstene 115,175di0l-3- one 17-acetate. I

By repeating this procedure using each of the steroid starting materialsjust mentioned and replacing acetic anhydride with propionic,cyclopentylpropionie and caproic anhydride, respectively, thecorresponding 17-propionates, -cyclopentylpropionates and -caproateswere obtained.

Example XXVII 19-nor-9B,10a-A -androstene-1 1,8,17B-diol-3-one17-acetate and 1rx-methyl-19-nor-9fi,10a-A -androstene-11,8,17,6-diol-3-one 17-acetate were oxidized, using chromium trioxide in pyridinein the manner described in Example VII hereinabove, thus giving19-nor-9/9,10a-A -androsten- 173-ol-3,11-dione 17-acetate and1a-methyl-19-nor-9fl,10u- A -androsten- 17 fl-o1-3, 1 l-dione17-acetate.

Example XX VIII The Hat-substituted steroids prepared as described inExample XXIV hereinabove were esterified, using acetic I tained.

15 anhydri-de in benzenein the presence of p-toluenesulfonic acid, andthe intermediate S-enol acetates were hydrolyzed, using methanolichydrochloric acid, in the manner described in Example XII hereinabove,thus giving 17a-methyl-19-n-or-9fl,10m-A -androstene-115,17,8-di01-3-one 1 1,17 -diacetate, 17a-ethyl-19-nor-9,B,10u-A-androstene-115,17,8-diol-3- one 11,17-diacetate,17a-viny1-19-nor-9B,l0a-Aandrostene-l1B,17fi-diol-3 one 11,17-diacetate,17a-ethynyl-19-nor-9B,10oa-A -androstene-11,8,17fi-diol-3- one11,17-diacetate, 17a-propargyl19-nor-9B,1Oa-A -androstene-115,17fl-diol-3-one 11,17-diacetate, 1a,17ol-dimethyl-9-nor-9fi,l0a-A-androstene-11,3,17,8-

diol-3-one -1 1,17-diacetate, 1a-methyl-17a-ethyl-l9-nor-9B,10a-A-androstene-1 1 5,

17,8-diol-3-one 11,17-diacetate, 1a-methyl-17a-vinyl-19-nor-9B,10u-A-androstene-115,

17.;8-diol-3-one 11,17-diacetate, 1a-methyl-17a-ethynyl-19-nor-9B,10a-A-androstene-1 1,8,

17fi-diol-3-one 11,17-diacetate, and1a-methyl-17a-propargyl-19-nor-9fi,10a-A -androstene- 115,17B-diol-3-oue 1 1,17-diacetate, respectively.

By repeating this entire procedure using propionic,cyclopentylpropionic, and caproic anhydrides in place of aceticanhydride, the corresponding 11,17-dipropionates,-dicyclopentylpropionates and -dicaprates were obtained.

Exam-ple XXIX A suspension of 1 gram of 17u-methyl-19-nor-9p,10a- A-androstene-11fl,17,8-diol-3-one 11,17-diacetate in 60 cc. of methanolwas admixed with a solution of 1 gram of potassium bicarbonate in 6 cc.of Water, and the resulting reaction mixture was allowed to stand at 0C. for 18 hours. Following this reaction period the reaction mixture wasdiluted with water and the resulting precipitate was collected byfiltration, washed with water and dried. Recrystallization fromacetone/hexane gave 17a-rnethyl-19- nor-9B,lfla-A -androstene-11B,l7/3-diol-3-one l7-acetate.

By repeating this procedure using the remaining 11,17- diacetates,-dipropionates, -dicyclopentylpropionates and -dicapr0ates prepared asdescribed in Example XXVIII hereinabove, the corresponding 17-monoesterswere ob- Example XXX The l7-rnonoacetates prepared as described inExample XXIX hereinabove were oxidized, using chromium trioxide inpyridine in the manner described in Example VII hereinabove, thus giving17-acetate, 17u-ethynyl-19-nor-9;3,10a-M-androsten-175-01-3,1 1-

dione l7-acetate,

. 17a-propargyl-19-nor-9,8,10a-A -an-drosten-1719-01-3,l1-

dione 17- acetate,

16' 1oz,17oc-dim6thyl-l9-11Or-9fi,10cz-A -al1dl'OSt6n-17B-Ol-3 ,11-

dione 17-acetate, la-methyl-lh-ethyl-l9-nor-9fi,l0u-A-andr0sten-17fl-ol- 3,11dione 17-acetate, 1a-methyl-l7a-vinyl-l9-nor-9f3,10a-A androsten-17fi-0l- 3,11-dione 17-acetate,1ot-methyl-17ot-ethynyl-19-nor-9B,1Oa-A -androsten-175- ol-3,11-dione17-acetate, and 1lat-methyl-17oc-pr0pargy1-19-nor-9fl,1Oa-A -androsten-17fl-ol-3,11-dione 17-acetate, respectively.

Example XXXI 3-methoxy-17-cycloethylenedioxy-9p A estratrien-ll 6-01 and1-methyl-3-methoxy-17-cycl'oethylenedicity-A -estratrien-1 1,8-01,prepared as described in Example XIX hereinabove, were treated withlithium in liquid ammonia in the manner described in Example Vhereinabove, thus giving 3-meth0xy-17-cycloethy1enedi oxy-9/3-A-estradien-1lfi-ol and the corresponding 1- methyl compound. ExampleXXXII The A -dienes prepared as described in Example XXXI hereina-bovewere hydrolyzed in the manner described in Example VI, hereinabove, thusgiving 19-nor- 9B,10a-A -androsten-11,B-ol-3,17-dione and 1a-methyl-19-nor-9 6, lOa-N-androsten-l 1B-ol-3,17-dione,

It will be obvious to those skilled in the art that other changes andvariations can be made in carrying out the present invention withoutdeparting from the spirit and scope thereof as defined in the appendedclaims.

We claim:

1. 1a,17a-dimethyl-19-nor-9B,10a-A -androsten-17 3-ol- 3-one.

2. laethyl-17a-ethynyl-19-nor-9,8,IOa-A -androsten- 17fl-0l-3-one.

3. 19-nor-9p, 1 Oa-N-androstene-B, 1 1,17-tri0ne.

5. 17ot-methyl-19-nor-9,8,10a-A androstene 1113,176- dio1-3-one.

, 6. 17a-methyl-19-nor-918,10a-A androstene 11 3,175- diol-3-onel7-ace'tate.

7. 17a-ethynyl-l9-nor-9fi,10u-A androstene 115,175- diol-3-one.

8. 17a-ethynyl-19-nor-9f3,10a-A -androstene 115,175- diol-3-one17-acetate.

9. l7a-rnethyll9-nor-9fi,10a-A -androsten-17fi-ol-3 ,1 ldione17-acetate.

1i). 17a-ethynyl-19-nor-9,8,10a-A -androsten-17/3-ol 3, ll-dione17-acetate.

References Cited UNITED STATES PATENTS 3,138,617 6/1964 Nomine et a1260-345.2 3,198,792 8/1965 Reerink et al 260239.55

OTHER REFERENCES Legrand et al., Compt. Rend. Acad. Sci. (1962'), pages322-324..

ELBERT L. ROBERTS, Primary Examiner. LEWIS GOTTS, Examiner.

3. 19-NOR-9B,10A-$4-ANDROSTENE-3,11,17-TRIONE.